Bottom Line:
In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice.Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

Background: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients

Methodology/principal findings: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRbeta1-expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.

Conclusions/significance: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

pone-0006428-g009: Hypothyroidism enhances formation of experimental lung metastasis.Control and hypothyroid mice were injected with parental and TRβ1-expressing cells into the tail vein and 30 days later lungs were excised mounted and stained. (A and C)-Representative images of lungs from mice injected with MDA, MDA-TRβ, SK and SK-TRβ cells. Metastasis are delineated with a discontinuous blue line. (B and D)-The percentage of animals bearing metastatic lesions, the number of lesions/lung, and the area of lung parenchyma affected (mean±S.E) were determined in the different groups.

Mentions:
The influence of hypothyroidism on formation of experimental metastasis was examined by comparing the appearance of lung metastasis upon inoculation of parental and TRβ-expressing cells into the tail vein of normal nude mice and mice treated previously with anti-thyroidal drugs. In agreement with our previous observations [22], most normal animals injected with parental SK cells developed nodular metastasis in the lungs, whereas less than 20% of the animals injected with SK-TRβ cells developed metastasis (Figure 9A and B). Hypothyroidism significantly increased the incidence of lung metastasis and under these conditions up to 70% of mice inoculated with TRβ-expressing cells had metastatic lesions. The number of metastasis per lung was also strongly enhanced in hypothyroid mice injected with either parental or SK-TRβ cells and the same occurred with the area of the tissue affected (Figure 9B).

pone-0006428-g009: Hypothyroidism enhances formation of experimental lung metastasis.Control and hypothyroid mice were injected with parental and TRβ1-expressing cells into the tail vein and 30 days later lungs were excised mounted and stained. (A and C)-Representative images of lungs from mice injected with MDA, MDA-TRβ, SK and SK-TRβ cells. Metastasis are delineated with a discontinuous blue line. (B and D)-The percentage of animals bearing metastatic lesions, the number of lesions/lung, and the area of lung parenchyma affected (mean±S.E) were determined in the different groups.

Mentions:
The influence of hypothyroidism on formation of experimental metastasis was examined by comparing the appearance of lung metastasis upon inoculation of parental and TRβ-expressing cells into the tail vein of normal nude mice and mice treated previously with anti-thyroidal drugs. In agreement with our previous observations [22], most normal animals injected with parental SK cells developed nodular metastasis in the lungs, whereas less than 20% of the animals injected with SK-TRβ cells developed metastasis (Figure 9A and B). Hypothyroidism significantly increased the incidence of lung metastasis and under these conditions up to 70% of mice inoculated with TRβ-expressing cells had metastatic lesions. The number of metastasis per lung was also strongly enhanced in hypothyroid mice injected with either parental or SK-TRβ cells and the same occurred with the area of the tissue affected (Figure 9B).

Bottom Line:
In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice.Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.

Background: Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients

Methodology/principal findings: In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRbeta1-expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRbeta-expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs.

Conclusions/significance: These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer.